The present invention covers a series of isotopically-labeled fluorenamine, dibenzofuranamine, and dibenzothiophenamine derivatives useful in the diagnosis of neurodegenerative disorders.
U.S. Pat. No. 3,159,677, 3,206,480 and 3,111,527 cover unlabeled fluorenamines, dibenzofuranamines, dibenzothiophenamines and processes for preparing them. The compounds are disclosed as having useful central nervous system depressant activity.
In Science, 227, 1496-1499 (1985), alterations in L-glutamate binding have been observed in Alzheimer's disease (AD; including primary degenerative dementia (PDD), senile dementia of the Alzheimer type (SDAT), and chronic organic brain syndrome (OBS)) and Huntington's (HD) disease, amongst other neurodegenerative disorders. Additional candidate disorders include, for example, Age-Associated Memory Impairment (AAMI; Dev Neuropsychol, 2, 261-276 (1986); including benign senescent forgetfulness (BSF) and mild-memory impairment (MMI)), and the constellation of disorders that can be described as Senile Cognitive Decline (SCD; J Med Chem, 29, 1125-1130 (1986); Annu Rep Med Chem, 21, 31-40 (1986); Med Res Rev, 8, 353-391 (1988)).
Glutamate is the putative neurotransmitter of both intracortical association fibers and cortical efferents to many subcortical structures, including caudate and putamen. Because glutamate and some of its analogues are neurotoxic, it has been proposed that abnormalities in glutamate neurotransmitter function may play a causative role in neurodegenerative disorders such as HD and olivopontocerebellar atrophy. Furthermore, a high correlation has been observed between the localization of 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), an analogue of phencyclidine (PCP), binding sites and N-methyl-D-aspartate (NMDA), a glutamate analogue, receptors in Eur J Pharmacol, 123, 173-174 (1986). Finally, a loss of hippocampal TCP binding in AD has been reported in Neurosci Lett, 74, 371-376 (1987).
TABLE 1 ______________________________________ Some Stable and Radioactive Isotopes Relative Maximum natural Decay mode specific Iso- abund- (type of activity tope ance radiation) Half-life (Ci/mol) ______________________________________ .sup. 2 H 0.0154 stable .sup. 3 H .beta.- 12.35 years 2.90 .times. 10.sup.4 .sup.11 C .beta.+ 20.3 minutes 9.22 .times. 10.sup.9 .sup.13 C 1.1 stable .sup.14 C .beta.- 5,730 years 62.4 .sup.13 N .beta.+ 9.96 minutes 1.89 .times. 10.sup.10 .sup.15 N 0.365 stable .sup.15 O .beta.+ 2 minutes 9.25 .times. 10.sup.10 .sup.18 O 0.204 stable .sup.18 F .beta.+ 109.7 minutes 1.71 .times. 10.sup.9 .sup.35 S .beta.- 87.1 days 1.5 .times. 10.sup.6 .sup. 36 Cl .beta.- 3.1 .times. 10.sup.5 years .sup.122 I.sup. gamma 3.6 minutes .sup.123 I.sup. gamma 13.3 hours .sup.131 I.sup. .beta.-, gamma 8 days ______________________________________
As shown in Table 1 above a variety of stable- and radio-active isotopes are of interest in the instant invention. Certain isotope terminologies are equivalent, and are used herein interchangeably, for example, .sup.2 H=H-2=D=deuterium; .sup.3 H=H-3=T=tritium. Further information on isotopes can be found in The Merck Index, Tenth Edition (Merck; Rahway, New Jersey: 1983), edited by M. Windholz et al.
Additional background information can be found in Synthesis and Applications of Isotopically Labeled Compounds, Proceedings of an International Symposium, Kansas City, MO, June 6-11, 1982 (Elsevier; Amsterdam, Netherlands: 1983), edited by W. P. Duncan and A. B. Susan.